Search Results (3,210)

Metformin is a widely prescribed antidiabetic agent with pleiotropic effects extending beyond glycemic control, including anti-inflammatory and antioxidant actions. However, its impact on cytokine signaling and ferroptosis-related pathways in brown adipose tissue (BAT) remains poorly characterized. Here, we examined the transcriptional and metabolic responses to metformin in brown adipocytes and in a diet-induced obesity model. Differentiated brown adipocytes were treated with metformin and analyzed by RNA sequencing and RT-qPCR. C57BL/6 male mice fed a high-fat diet (HFD) were administered metformin to assess systemic metabolic parameters and BAT-specific responses, with validation by histology, RT-qPCR, and Western blot. Transcriptomic profiling identified differentially expressed genes enriched in cytokine–cytokine receptor interaction and ferroptosis-related KEGG pathways. Metformin modulated the expression of multiple inflammatory cytokine genes and upregulated antioxidant and ferroptosis defense-related genes, including the glutathione biosynthesis genes Gclc and Gclm, together with Hmox1, Gpx4, Nfe2l2 (Nrf2), and Slc7a11. Among these, Gpx4 showed the most consistent upregulation across mRNA and protein levels in BAT. In HFD-fed mice, metformin improved glucose tolerance and elevated the expression of antioxidant and ferroptosis-related genes in BAT, consistent with the in vitro findings. Together, these results indicate that metformin coordinately modulates antioxidant and ferroptosis defense-related gene expression in BAT, suggesting a tissue-protective transcriptional program under metabolic stress. Our findings identify candidate immunometabolic and ferroptosis-related targets of metformin in BAT and provide a basis for further mechanistic investigation of its tissue-specific actions beyond glycemic control. Full article

Background/Objectives: Communication training in undergraduate nursing skills courses is often overshadowed by procedural skill acquisition, leaving limited opportunities for students to develop patient-centered communication skills and engage in reflective learning. This study evaluated a reflection-integrated CICARE communication program embedded in a Fundamentals of Nursing skills course and explored students’ learning experiences. Methods: A quasi-experimental study with an embedded qualitative component was conducted among second-year undergraduate nursing students in China. The quantitative component used a non-equivalent control group design, while reflective journals from the Intervention Group provided qualitative data on students’ learning experiences. Two intact classes were assigned to the Intervention Group (n = 65), and two intact classes were assigned to the Control Group (n = 66). The Intervention Group received an 18-week CICARE-based communication program integrated into skills training, including scenario-based role-play, emotional cue recognition, demonstration videos, feedback, and reflective journals. The Control Group received conventional skills training. Outcomes included communication competence, empathy, professional identity, clinical judgment, and course performance. Analysis of covariance was used to compare post-intervention outcomes after adjustment for baseline scores. Reflective journals from the Intervention Group were analyzed thematically. Results: After adjustment for baseline scores, the Intervention Group showed significantly higher communication competence than the Control Group (adjusted mean difference = 2.699, 95% CI: 0.108–5.291, p = 0.041). Empathy was also higher in the Intervention Group (adjusted mean difference = 3.796, 95% CI: 0.538–7.053, p = 0.023). The between-group difference in professional identity was not statistically significant (p = 0.073). The Intervention Group achieved higher total clinical judgment scores than the Control Group (31.52 ± 5.50 vs. 27.20 ± 6.45, p < 0.001), with significant differences in noticing, interpreting, and reflecting. Course performance was also higher in the Intervention Group. In their reflective journals, students described greater patient-centered awareness, attention to patients’ emotional needs, professional reflection, and motivation for self-directed learning. Conclusions: Integrating CICARE-based communication training with reflective learning may strengthen communication competence, empathy, clinical judgment, and course performance in undergraduate nursing skills education. Further studies with longer follow-up are needed to determine whether the observed differences persist over time and whether professional identity and action-oriented clinical responses improve with longer educational exposure. Registration: This study was not registered. Full article

Leaf senescence is a highly programmed developmental process that enables nutrient remobilization from source to sink organs in plants. Chloroplasts serve as the primary nitrogen reservoir, and the timely degradation of their constituent proteins is essential for sustaining seed fill and crop yield. For efficient nitrogen recycling, the chloroplast proteome must be dismantled in a controlled manner through coordinated proteolytic pathways that function both inside and outside the organelle. Protein abundances are progressively reduced during senescence through the balanced action of degradation and the suppression of new synthesis, depending on the plant’s carbon–nitrogen status. Malfunctioning or damaged chloroplast components are selectively eliminated. To date, three major classes of chloroplast protein degradation systems have been characterized: the cytoplasmic ubiquitin–proteasome system (UPS), vacuolar degradation pathways, and intra-chloroplast proteases. Here we provide an updated, comprehensive overview of the three chloroplast protein degradation machineries and discuss their coordinated roles in nitrogen remobilization. We also consider how these pathways might be manipulated to improve nitrogen use efficiency (NUE) and crop productivity. Full article

Background: Clinical pharmacists play a crucial role in identifying and resolving drug-related problems (DRPs) in hospitals. However, there is limited empirical evidence concerning their effect on service organizations in smaller regional facilities in Saudi Arabia. Methods: A retrospective serial cross-sectional study was conducted using three years of administrative data (2023–2025) from two public hospitals in the Al-Baha region. A total of 1812 different database records were identified after full-scale data cleaning, validation, and deduplication. The statistical framework included chi-square test of independence, pairwise two-proportions Z-test, three multivariate binary logistic regression models, Cramer’s V association analysis, and Ward’s hierarchical cluster modeling. Results: Active intervention rates significantly increased from 48.9% in 2023 to 72.4% in 2024 (z = −8.58, p < 0.001), stabilizing at 69.6% throughout 2025 (p < 0.001 versus the 2023 baseline), because 2023 data came from a different source system than 2024 to 2025 data, this pattern is reported descriptively rather as a programmatic integration. The most frequent clinical actions addressed therapy optimization (28.4%), inappropriate dosage regimens (23.6%), and missing drug orders (18.8%). Most entries recorded were for adult intensive care units (ICUs) (74.1%), and most involved patients aged 65 years or older (61.1% of records). ICU setting was independently associated with the intervention being classified as therapy optimization (adjusted odds ratio [aOR] 2.64, p < 0.001), but it was an inverse predictor of dosage-error tracking (OR 0.30, p < 0.001). Conclusions: This is among the first serial cross-sectional studies to build an evidence-based framework describing clinical pharmacy practices in the Al-Baha region, showing pharmacists’ roles and prioritizing advanced clinical training programs, reinforcing the need for critical analysis of health cluster policies across peripheral Saudi networks. Full article

Background: Combat sports require athletes to repeatedly perform explosive actions under conditions of fatigue, demanding high levels of neuromuscular coordination, reactive agility, and intermittent effort capacity. This study examined changes in biomechanical and neuromuscular performance over a 15-week period during which competitive Sambo athletes completed a CrossFit-based functional training program alongside their regular sport-specific training. Methods: Forty male Sambo athletes (22.4 ± 2.6 years) completed a longitudinal repeated-measures intervention consisting of three weekly CrossFit-based sessions integrated into regular sport-specific training. The program was periodized across four progressive mesocycles emphasizing functional strength, explosive power, reactive agility, and fatigue resistance. Pre- and post-intervention assessments included upper- and lower-limb reaction speed, vertical jump height, repeated jump endurance, reactive agility, grip endurance, body-weight squat performance, Romanian deadlift repetitions, and the Special Judo Fitness Test (SJFT). Statistical analyses included paired-samples t-tests or Wilcoxon signed-rank tests with Benjamini–Hochberg false discovery rate correction (α = 0.05). Results: Significant post-intervention improvements were observed in most performance variables. Upper- and lower-limb reaction performance improved by 22.9% and 9.7%, respectively (p < 0.001), while vertical jump height increased by 11.4% and repeated jump endurance by 16.6% (p < 0.001). Reactive agility time decreased by 6.6% (p < 0.001), indicating faster cognitive-motor responsiveness. Functional strength improved substantially, with increases of 43.7% in body-weight squat performance and 71.9% in Romanian deadlift repetitions (p ≤ 0.001). Grip endurance improved by 6.3% (p = 0.007), whereas maximal handgrip strength showed no significant changes. The SJFT index decreased by 5.0% (p < 0.001), reflecting enhanced intermittent effort efficiency and fatigue tolerance. Large effect sizes were identified for upper-limb reaction speed (d = 1.42), explosive endurance (d = 1.46), and reactive agility (d = 0.96). Conclusions: Over the 15-week study period, participation in a CrossFit-based functional training program integrated into regular Sambo practice was associated with improvements in several biomechanical and neuromuscular performance outcomes, including reaction performance, explosive power, agility, muscular endurance, and sport-specific work capacity. However, because the study did not include a control group, these changes cannot be attributed exclusively to the CrossFit-based intervention. Controlled studies are required to distinguish intervention-specific effects from seasonal training adaptations, continued sport-specific practice, and test familiarization. Full article

Background/Objectives: Ciliary neurotrophic factor (CNTF), a pleiotropic cytokine with central and peripheral actions, has been implicated in obesity, insulin resistance, and aging, yet its role in skeletal muscle and cardiometabolic health remains unclear. This study examined skeletal muscle CNTF mRNA expression in relation to adiposity and glucose tolerance in older adults and assessed the effects of six-month weight loss (WL) and aerobic exercise training (AEX) interventions on its expression. Methods: Sixty-seven adults (age, 60.75 ± 7.58) underwent a vastus lateralis muscle biopsy, VO₂max testing, dual-energy X-ray absorptiometry (DXA) scan, a resting metabolic rate (RMR) and substrate oxidation assessment, and a 3-h oral glucose tolerance test with glucose and insulin area under the curve (AUC) calculation. A subset completed 6 months of either a WL program (n = 21) or a supervised 3 times per week AEX intervention (n = 20). Results: At baseline, skeletal muscle CNTF expression was inversely associated with RMR, fat oxidation, 3-h glucose AUC, and insulin AUC, but not with BMI, percent body fat, or VO₂max. WL reduced body weight, fat mass, glucose AUC, insulin AUC, and basal muscle CNTF expression, whereas AEX increased VO₂max and reduced fat mass without altering body weight, glucose AUC, insulin AUC, or basal CNTF. Insulin-stimulated CNTF expression increased after both WL and AEX, and the intervention-induced change in glucose disposal (M) was positively associated with the change in insulin-stimulated CNTF. Conclusions: In older adults, skeletal muscle CNTF is associated with glucose intolerance but is not associated with body composition or aerobic fitness. Improvements in insulin sensitivity are associated with increases in muscle CNTF during hyperinsulinemia. Further work is needed to determine the mechanism for muscle CNTF change during hyperinsulinemia after weight loss and exercise training, and its role in glucose metabolism and obesity in older adults. Full article

Purpose: This study investigates the structural pathways driving the startup potential of Generation Z students in Romania’s post-transition economy. It examines the sequential relationship between Entrepreneurial Mindset (EM), Entrepreneurial Intentions (EIs), and Entrepreneurial Behavior (EB), focusing on the mediating role of intentions in bridging the gap between cognition and action. Design/methodology/approach: Using a quantitative explanatory design, data were collected through a two-stage hybrid framework from a sample of 215 Romanian business students associated with the Hackathon Innovation Labs (HILs), selected via a non-probability purposive sampling method. Hypotheses were tested using Structural Equation Modeling (SEM) with maximum likelihood estimation, supported by Confirmatory Factor Analysis (CFA) to ensure statistical rigor. Findings: Results confirm that EM is a robust predictor of EI, which significantly drives EB, explaining 45.2% of its variance. The findings highlight that intentions fully mediate the relationship, suggesting that a growth-oriented mindset turns into firm intentions to overcome institutional and cultural barriers. Originality: This research applies a rigorous SEM framework to a cohort of digital natives in an underrepresented Eastern European emerging market. It integrates mindset as a foundational cognitive precursor and provides empirical evidence of the sequential path to entrepreneurial behavior. Research limitations/implications: The study is limited by its sample size and geographic focus on Romanian business students. Future longitudinal research should explore external contingency factors, such as access to capital and ecosystem support, to validate model generalizability. Practical and social implications: Higher education should shift toward experiential programs like HILs, embedding credit-bearing hackathons and micro-credentials to foster an entrepreneurial mindset. Socially, sustaining this momentum with structured mentorship bridges the intention–action gap, transforming Gen Z’s digital potential into tangible economic value for the post-transition ecosystem. Full article

Sepsis-associated acute lung injury (SALI) is characterized by disruption of the alveolar–capillary barrier, uncontrolled inflammation, oxidative stress, and impaired tissue repair. Ferroptosis and cellular senescence have emerged as potentially interacting stress-response programs that may jointly shape the progression of septic lung injury. Ferroptosis promotes epithelial and endothelial damage through iron-dependent lipid peroxidation, glutathione depletion, and impaired GPX4-mediated lipid repair. In parallel, senescence-associated remodeling may contribute to persistent cell-cycle arrest, senescence-associated secretory phenotype (SASP) production, endothelial dysfunction, and defective regenerative capacity. This review summarizes current evidence on the molecular and cellular crosstalk between ferroptosis and cellular senescence in SALI. Candidate regulatory intersections include context-dependent mitochondrial dysfunction, reactive oxygen species accumulation, iron dyshomeostasis, metabolic reprogramming, lysosomal dysfunction, DNA-damage responses, and stress-responsive pathways involving p53, NRF2, ATF4, STAT3, and FOXO1. Direct SALI evidence is currently strongest for ferroptosis-induced senescence-associated remodeling in pulmonary endothelial cells, whereas senescence-associated ferroptosis resistance is supported mainly by non-pulmonary models. Likewise, SASP-mediated paracrine ferroptosis in neighboring pulmonary cells remains insufficiently validated. We therefore propose an evidence-informed, temporally and cell-type-dependent ferroptosis–senescence framework in SALI, in which acute senescence-associated responses may coexist with ferroptotic injury, whereas persistent senescence-associated remodeling may contribute to defective repair and microenvironmental injury amplification. Targeting this axis through ferroptosis inhibition, restoration of endogenous antioxidant defenses, senotherapeutic modulation, and regenerative strategies may offer stage-informed therapeutic opportunities. Further time-resolved and cell-specific studies are required to define causal relationships and clinically actionable therapeutic windows. Full article

We examine whether simulated attack-action evidence can inform a defender that they must commit before an attacker’s type is known. We formulate a five-stage Bayesian Stackelberg security game with five stage-specific actions per player. A Monte Carlo predictor produces type-conditioned action likelihoods on an enterprise graph, while prediction confidence weights the next Bayesian update. The defender strategy is computed by exact follower-response enumeration and linear programming. Evaluation used a simulated 10-node enterprise network, 30 paired trials, bootstrap confidence intervals, and Holm-adjusted Wilcoxon tests. Against a fixed-prior Bayesian Strong Stackelberg Equilibrium, mean gross defense utility increased from 2.141 to 2.197. Mean attack success decreased from 0.691 to 0.686. The paired differences remained significant after multiplicity correction. Outcomes did not differ significantly from an equilibrium updated with coarse reference likelihoods, and the simulation cost reduced net utility by 0.08. Maximum follower regret and constraint violation remained at the specified numerical tolerance. Runtime remained near 0.39 s across networks of 10–100 nodes. An action/type experiment showed rapid growth as follower-response profiles increased. Exact commitment and sequential updating were feasible in the abstraction; simulation was not automatically cost-effective when a usable reference model was available. Full article

The redox state of the nucleus is emerging as a critical determinant of plant cell fate: reactive oxygen species (ROS) signals that originate in chloroplasts, peroxisomes, and the apoplast ultimately converge on nuclear proteins that determine whether a cell mounts a protective response or initiates programmed cell death (PCD). Loss-of-function mutations in ATR7, which encodes a nuclear protein specific to seed plants, confer tolerance to both paraquat- and aminotriazole-induced cell death, establishing ATR7 as a positive regulator of ROS-induced PCD. Yet how ATR7 acts at the molecular level remains unknown. In this paper, we define the ATR7 protein interactome using IP-MS of GFP-tagged ATR7 and integrate it with the atr7 loss-of-function transcriptome to distinguish it as candidate direct molecular partners from transcriptionally regulated targets. To investigate the nuclear protein association with ATR7, we performed GFP affinity purification followed by mass spectrometry (IP-MS) using Arabidopsis thaliana seedlings expressing GFP-ATR7, in comparison with seedlings expressing free GFP as the negative control. The IP-MS candidates were compared with the previously published ATR7 transcriptome data. ATR7 associates with chromatin-modifying proteins, components of the ubiquitin–proteasome system, and a broad set of stress-responsive proteins whose encoding genes are constitutively de-repressed when ATR7 is non-functional. Among the candidate proteins are those that have potential chromatin-regulatory functions, including AT1G01920 (a SET-domain protein) and HDA14, as well as components associated with ubiquitin–proteasome pathways and oxidative stress responses. Several interactors have no current functional annotation and represent candidates for novel roles in oxidative stress signalling. These findings provide the first mechanistic framework for ATR7 action and implicate nuclear chromatin-level repression as a key node in the regulation of ROS-induced PCD in plants. Full article

Background: Poor adherence to home exercise programs is a persistent challenge in physical rehabilitation and beyond. Data suggest that follow-up telehealth visits featuring behavior change techniques can improve adherence. However, the optimal frequency of behavioral support for effective self-management of technology-enabled home exercise programs remains unclear. This paper investigates how adherence to home exercise varies with the number of follow-up visits holding the type of exercise constant and measuring adherence objectively. Methods: A secondary analysis of adherence was conducted on participants from the VIGOROUS five-site, single-blind, and randomized controlled trial. Chronic (>6 months) community-resident stroke survivors with mild-to-moderate upper extremity hemiparesis (n = 111) were assigned 15 h of asynchronous video game-based home exercise over 3 weeks. Participants received behavioral support during (a) one single in-person session, (b) four in-person sessions, or (c) four in-person sessions plus six remote teleconsultations. Each consultation incorporated standardized behavior change techniques—contracting, feedback, self-monitoring, action planning, and guided problem solving—to promote increased paretic arm use during daily activities. The primary outcome was adherence (minutes exercising), objectively captured by the gaming system for 87 participants. Results: Six telehealth visits with remote therapeutic monitoring (RTM) increased home exercise completion by 3.3 h [95% CI: 0.008, 6.60]; each remote or in-person consultation was associated with an estimated 34 min of additional asynchronous home exercise. Conclusions: RTM, which does not require travel to a healthcare facility, is a time-efficient modality to enhance therapeutic engagement. Behaviorally focused telehealth visits boost stroke survivors’ adherence to a structured home exercise program. Full article

Background/Objectives: Drowning among children younger than five years remains a major public health problem in Thailand, particularly in residential water environments. Caregivers’ supervision and home safety practices play an important role in preventing childhood drowning. This study evaluated the association between participation in the Be SAFE Program, a community-based educational intervention developed using the Health Belief Model (HBM), and changes in caregivers’ health beliefs and self-reported drowning prevention behaviors. Methods: A quasi-experimental pretest–posttest control group study was conducted among 60 caregivers of children younger than five years recruited from two community settings in Ubon Ratchathani Province, Thailand. Participants were assigned to either an intervention group (n = 30) or a control group (n = 30). The intervention group participated in the HBM-based Be SAFE Program, whereas the control group received routine care. Outcomes included HBM constructs and self-reported drowning prevention behaviors. Baseline-adjusted analyses of covariance (ANCOVA) were performed to compare post-intervention outcomes between groups. Holm adjustment was applied to account for multiple comparisons. Results: After adjustment for baseline scores, caregivers in the intervention group demonstrated significantly greater improvements than those in the control group in perceived susceptibility, perceived severity, perceived benefits, cues to action, self-efficacy, and self-reported drowning prevention behaviors, together with significantly lower perceived barriers (all Holm-adjusted p < 0.05). Large effect sizes were observed across all measured outcomes. Conclusions: The findings suggest that the HBM-based Be SAFE Program was associated with greater short-term improvements in caregivers’ health beliefs and self-reported drowning prevention behaviors than routine care. These findings support the potential value of theory-based community educational programs for childhood drowning prevention while highlighting the need for larger multi-site studies with longer follow-up to confirm the program’s effectiveness and broader applicability. Full article

Decarbonizing the transportation sector depends not only on the scale of mitigation programs but also on whether financing systems are capable of generating measurable emission reductions. In Indonesia, climate finance allocation remains substantially below the level required to achieve the transportation-sector target under the Enhanced Nationally Determined Contribution (ENDC). At the same time, mitigation planning rarely establishes a clear relationship between financial expenditure and verified greenhouse gas (GHG) reduction outcomes, making policy effectiveness difficult to assess. This study examines the relationship between climate finance and mitigation outcomes in Indonesia’s transportation sector using verified emission reduction data and realized mitigation expenditures during 2018–2022. A cost-based assessment approach was applied to estimate the financing required to reduce one ton of CO₂ equivalent (tCO₂-e) across direct and indirect mitigation actions. The analysis identified 33 mitigation actions categorized under the Avoid–Shift–Improve (ASI) framework and evaluated their contribution to sectoral emission reduction. The results indicate substantial variation in mitigation costs among intervention types. Direct mitigation actions, particularly mass public transportation expansion, are linked to larger emission reductions at relatively lower costs than enabling or indirect measures. On average, reducing 1 tCO₂-e in Indonesia’s transportation sector requires approximately USD 184–1000 (IDR 3–16.4 million), using a standardized exchange rate of approximately IDR 16,400 per USD. Based on the transportation-sector ENDC target, the estimated financing requirement by 2030 ranges from USD 2.5–13.8 billion (IDR 42–226 trillion). The findings suggest that climate finance policies should move beyond expenditure-oriented approaches toward financing frameworks that explicitly connect investment allocation with verified mitigation performance. Full article

Spinal cord stimulation (SCS) is a widely used neuromodulatory therapy for chronic neuropathic pain, yet the cellular and molecular mechanisms underlying its clinical efficacy remain incompletely understood. This review synthesizes current literature on the neurophysiology of pain transmission and the mechanistic basis of major SCS paradigms (tonic, high-frequency, burst, and closed-loop stimulation), highlighting how each modality engages distinct dorsal horn circuits, glial and inflammatory pathways, as well as supraspinal networks involved in the affective dimension of pain. Particular attention is given to the evoked compound action potential (ECAP) as an emerging electrophysiological biomarker that enables real-time, feedback-guided stimulation and offers insight into the biophysical determinants of dorsal column activation. We also examine preclinical and clinical evidence linking SCS to modulation of central sensitization, neuroinflammatory signaling, and autonomic regulation, while identifying persistent gaps in mechanistic understanding. Finally, we discuss future directions, including AI-assisted, personalized SCS programming and expanding indications beyond classical neuropathic pain, underscoring the need for multimodal experimental approaches to more precisely define how SCS achieves analgesia. Full article

First-year students in STEM programs face significant academic and personal challenges that can undermine retention and success, particularly for those navigating new institutional environments without prior college experience. While self- regulated learning (SRL) theory offers a well-established framework for understanding how students plan and reflect, less attention has been paid to the performance phase, the stage where students must translate plans into action amid real academic and social demands. This qualitative study examines the experiences of 15 first-year life science students across three institution types, a Hispanic-Serving Institution, a predominantly white institution, and a liberal arts college, to investigate what plans students formed at the end of their first semester and what factors facilitated or hindered implementation during their second semester. Using thematic analysis of semi-structured interviews, three major plan themes emerged: help-seeking, internal academic adjustments, and managing social and emotional well-being. Facilitating factors for these plans included small class sizes, anonymized participation tools, approachable instructors, peer and family support, counseling services, and structured planning tools, while hindering factors included fear of judgment, high instructor-student ratios, scheduling conflicts, academic burnout, and unsupportive living environments. The findings reveal that plan implementation depended on the interplay of intersecting psychological, social, and structural factors, which created unique conditions that influenced whether students were able to enact their plans. Importantly, the findings reveal that plan implementation unfolded not as a linear process but through nested micro-cycles of forethought, performance, and reflection within the performance phase, triggered by specific events throughout the semester. These findings have implications for how institutions design learner-centered support for STEM students not only at key transition points, but also throughout the semester, to address the conditions that influence whether students are able to successfully implement, adapt, or abandon their regulatory efforts. Full article